Novel 1-(pyridylphenyl)-1-phenyl-2-imidazolylethanols with topical antiinflammatory activity

• Published in: Journal of medicinal chemistry Vol. 35; no. 17; pp. 3148 - 3155
• Main Authors: Wright, Stephen W, Harris, Richard R, Collins, Robert J, Corbett, Ronald L, Green, Alicia M, Wadman, Eric A, Batt, Douglas G
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01-08-1992
• Subjects: Administration, Topical; Animals; Anti-Inflammatory Agents - chemical synthesis; Anti-Inflammatory Agents - pharmacology; Anti-Inflammatory Agents - therapeutic use; Arachidonic Acid; Calcimycin; Chemistry; Cyclooxygenase Inhibitors - pharmacology; Dermatitis - drug therapy; Dermatitis - etiology; Edema - chemically induced; Edema - drug therapy; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings; Imidazoles - chemical synthesis; Imidazoles - pharmacology; Imidazoles - therapeutic use; Lipoxygenase Inhibitors - pharmacology; Male; Mice; Molecular Structure; Organic chemistry; Phospholipases A - antagonists & inhibitors; Preparations and properties; Pyridines - chemical synthesis; Pyridines - pharmacology; Pyridines - therapeutic use; Structure-Activity Relationship; Tetradecanoylphorbol Acetate; Non steroidal antiinflammatory agent; In vivo; Five membered ring; Nitrogen heterocycle; Tertiary alcohol; Six membered ring; Fluorine Organic compounds; Biological activity
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00095a009

The synthesis, biological evaluation, and structure-activity relationships of a series of 1-(pyridylphenyl)-1-phenyl-2-imidazolylethanols are described. These compounds show potent dose-dependent topical antiinflammatory activity in murine models of skin inflammation. This effect is likely due to inhibition of cytochrome P450 and consequent reduction in levels of 12R-HETE in the skin. These compounds were examined for their ability to inhibit the oxidative metabolism of arachidonic acid; they specifically inhibit the formation of prostacyclins in mouse macrophages. To study the effects of structure on the in vivo activity, three general features of the molecules were varied: the position of attachment of the pyridine nucleus (A), the second aromatic residue (B), and the nitrogen base on the ethanol chain (C). 1-[4-(4-Pyridyl)phenyl]-1-(4-fluorophenyl)-2- imidazolylethanol (2a, DuP 983) shows a very attractive profile of antiinflammatory activity and has been selected for clinical evaluation as a topical antiinflammatory agent.